Uveal melanoma (UM) is a subtype of melanoma characterized by the strong contribution of genetic rather than environmental factors in the pathogenesis of the disease, making it an ideal model disease to study the genetic basis of cancer. The long-term goal of our laboratory is to determine the genes and mechanisms responsible for hereditary cancer predisposition associated with UM. To accomplish this, we have collected a large cohort of UM patients with high risk of hereditary cancer predisposition. Our work to date with this cohort supports that germline inactivation of BAP1 and other gene(s), account for the hereditary cancer syndromes in a subset of UM patients. This will be tested with two specific aims, one focused on BAP1 studies and one on other candidate genes: Aim 1: Identify mechanisms of germline BAP1 inactivation in UM patients with clinical phenotype suggestive of tumor predisposition syndrome (TPDS). Aim 2: Identification of novel candidate genes contributing to hereditary predisposition to UM. Scientific and Translational Impact: Outcomes will include identification of molecular mechanisms of heritable germline inactivation in BAP1 in patients with UM. This will provide much needed information for genetic counseling of patients at risk of TPDS, especially now that this gene is being added to clinical genetic testing panels. Identification of additional candidate genes associated with hereditary predisposition to UM will lead to further studies by us and others to further characterize the clinical phenotype and potential targets for therapy of these syndromes